Autoimmune Primary Biliary Cirrhosis Research Articles

Autoantibodies in Overlapping Systemic Sclerosis and Primary Biliary Cirrhosis Autoimmune Diseases

Autoantibodies in Overlapping Systemic Sclerosis and Primary Biliary Cirrhosis Autoimmune Diseases

Environmental factors in primary biliary cirrhosis.

The etiology of the autoimmune liver disease primary biliary cirrhosis (PBC) remains largely unresolved, owing in large part to the complexity of interaction between environmental and genetic contributors underlying disease development. Observations of disease clustering, differences in geographical prevalence, and seasonality of diagnosis rates suggest the environmental component to PBC is strong, and epidemiological studies have consistently found cigarette smoking and history of urinary tract infection to be associated with PBC. Current evidence implicates molecular mimicry as a primary mechanism driving loss of tolerance and subsequent autoimmunity in PBC, yet other environmentally influenced disease processes are likely to be involved in pathogenesis. In this review, the authors provide an overview of current findings and touch on potential mechanisms behind the environmental component of PBC.

Follicular bronchiolitis as phenotype associated with CD25 deficiency

Regulatory T cells [Tregs ; CD4(+) CD25(+) forkhead box protein 3 (FoxP3(+) )] are subsets of T cells involved in the maintenance of peripheral self-tolerance by actively suppressing the activation and expansion of autoreactive T cells. Signalling through the interleukin-2 receptor (IL-2R) contributes to T cell tolerance by controlling three important aspects of regulatory T cell (Treg ) biology. CD25 is the α-chain of the IL-2R that, in concert with the β-chain and γ-chain, constitutes the complete IL-2R. CD25 contributes only to IL-2 binding affinity but not to the recruitment of signalling molecules. However, its importance in the development of a normal immune response is emphasized by the finding that a truncation mutant of CD25 results in an immunodeficiency in humans characterized by an increased susceptibility to viral, bacterial and fungal infections. In 1997, Sharfe et al. described an infant with severe bacterial, viral and fungal infections. Counts of autologous T lymphocytes were moderately low, T cells displayed a weak proliferative response to mitogens in vitro and the patient displayed no rejection of an allogeneic skin graft. However, unlike children with severe combined immunodeficiency (SCID), besides not having circulating T cells, the patient also developed peripheral lymphocytic proliferation and autoimmune primary biliary cirrhosis. We present the first female Argentine patient with mutation in CD25 associated with chronic and severe inflammatory lung disease (follicular bronchiolitis with lymphocyte hyperplasia), eczema and infections. She has no expression of CD25 on CD4(+) T cells and an extremely low amount of Tregs . The molecular study confirmed homozygous missense mutation in the alpha subunit of the IL-2 receptor (CD25αR) (c. 122 a > c; p. Y41S).

212 Exome Sequencing in Families Identifies Rare Variants in Cell Junction Associated Proteins Representing a Potential Link Between Genetic Variation and Liver-Targeted Autoimmunity in Primary Biliary Cirrhosis

212 Exome Sequencing in Families Identifies Rare Variants in Cell Junction Associated Proteins Representing a Potential Link Between Genetic Variation and Liver-Targeted Autoimmunity in Primary Biliary Cirrhosis

Role of autoimmunity in primary biliary cirrhosis

Primary biliary cirrhosis (PBC) is an autoimmune liver disease characterized by the presence of serum autoantibodies and chronic nonsuppurative destructive cholangitis. The pathogenesis of PBC involves environmental factors, genetic predisposition and loss of immune tolerance. In recent years, it has become univocally accepted that an inappropriately activated immune response is one of the most important factors in PBC. In this study, the role of autoimmunity in PBC is summarized and a feasible research orientation is recommended.

Environmental factors and the induction of autoimmunity in primary biliary cirrhosis

Primary biliary cirrhosis (PBC) is a chronic cholestatic disease with an autoimmune pathogenesis and an unknown etiology, predominantly affecting postmenopausal women. The term PBC is a misnomer since most cases currently diagnosed have limited probability to develop cirrhosis. Antimitochondrial autoantibodies, elevated IgM and selective destruction of the intrahepatic bile ducts are the hallmarks of PBC. A permissive genetic background is critical in producing susceptibility despite limited associations with alleles within the MHC. The disease has incomplete concordance in monozygotic twins and its geoepidemiology suggests a role for environmental factors in the induction of PBC. This hypothesis is further supported by clinical (risk factors) and experimental evidence. Some of the factors incriminated model molecular mimicry by infectious agents and xenobiotic chemicals. Additional candidates are being proposed through large screening; all proposed associations ultimately require confirmation in animal models and clinical practice.

Impaired indoleamine 2,3-dioxygenase production contributes to the development of autoimmunity in primary biliary cirrhosis

The immunomodulatory effects of the tryptophan-catabolizing enzyme indoleamine 2,3-dioxygenase (IDO) have been elucidated at a cellular level and implicated in the pathogenesis of several complex diseases. Defects within the regulatory T cell compartment are one of the characteristics of primary biliary cirrhosis (PBC), an autoimmune chronic cholestatic liver disease, a phenotype that has also been shown in disease-mimicking animal models of this disease. We hypothesized that IDO dysregulation could lead to altered frequency and/or function of T cells at the level of antigen processing/presentation and we thus investigated IDO in peripheral monocytes and bile duct cells from patients with PBC. Both expression and activation manifested an impaired IFN-γ response in peripheral monocytes while a peculiar IDO expression profile in bile duct cells characterized early stage PBC. Further, we observed an increased frequency of a gain-of-function SNP within the TGF-β promoter region, a molecule known to suppress IDO transcription. In conclusion, we submit that an impaired IDO induction characterizes PBC and might represent a contributing factor in disease pathogenesis in association with several specific defects in the target tissue.

Interacting alleles of the coinhibitory immunoreceptor genes cytotoxic T-lymphocyte antigen 4 and programmed cell-death 1 influence risk and features of primary biliary cirrhosis

Autoimmune diseases such as primary biliary cirrhosis (PBC) result from failure in the immune mechanisms that establish and maintain self-tolerance. Evidence suggests that these processes are shared among the spectrum of autoimmune syndromes and are likely genetically determined. Cytotoxic T-lymphocyte antigen 4 (CTLA4) and programmed cell-death 1 (PDCD1) are two genes encoding coinhibitory immunoreceptors that harbor polymorphisms with demonstrated associations to multiple autoimmune disorders. We aimed to assess functional single nucleotide polymorphisms (SNPs) in these two genes for association with PBC. SNPs in CTLA4 and PDCD1 were genotyped in 351 PBC patients and 205 controls. Allele and genotype frequencies were evaluated for association with PBC and/or antimitochondrial antibody (AMA) positivity with logistic regression. Haplotypes were inferred with an expectation-maximization algorithm, and allelic interaction was analyzed by logistic regression modeling. Individual SNPs demonstrated no association to PBC. However, the GG genotype of CTLA4 49AG was significantly associated with AMA positivity among the PBC patients. Also, individual SNPs and a haplotype of CTLA4 as well as a rare genotype of the PDCD1 SNP PD1.3 were associated with orthotopic liver transplantation. As well, we identified the influence of an interaction between the putatively autoimmune-protective CTLA4 49AG:CT60 AA haplotype and autoimmune-risk PDCD1 PD1.3 A allele on development of PBC. Our findings illustrate the complex nature of the genetically induced risk of PBC and emphasize the importance of considering definable subphenotypes of disease, such as AMA positivity, or definitive measures of disease severity/progression, like orthotopic liver transplantation, when genetic analyses are being performed. Comprehensive screening of genes involved with immune function will lead to a greater understanding of the genetic component of autoimmunity in PBC while furthering our understanding of the pathogenic properties of this enigmatic disease.

Autoreactive CD8‐specific T‐cell response in primary biliary cirrhosis

Primary biliary cirrhosis (PBC) is an autoimmune liver disease of unknown etiology. Autoimmune attack in PBC is predominantly organ-specific, despite the presence of mitochondrial autoantigens, the major targets of autoimmunity in PBC, in all nucleated cells. Cytotoxic T lymphocytes are thought to be directly involved in the tissue injury in PBC. The major histocompatibility complex (MHC) class I-restricted epitope for E2 components of pyruvate dehydrogenase complexes, namely amino acid 159-167, a region very close to the epitoperecognized by MHC class II-restricted CD4 cells and by antibody, has been characterized. In addition, there was a 10-fold increase in the frequency of autoreactive cytotoxic T lymphocytes in the liver as compared to the blood in PBC patients using tetramer technology.

Origin of cross‐reactive autoimmunity in primary biliary cirrhosis

Origin of cross‐reactive autoimmunity in primary biliary cirrhosis

Mitochondrial Antigens as Targets of Cellular and Humoral Auto-Immunity in Primary Biliary Cirrhosis

Several factors point toward an auto-immune pathogenesis for primary biliary cirrhosis(PBC), mostly based on the presence of serum auto-antibodies to mitochondrial antigens(AMAs) and autoreactive T cells (both helper and cytotoxic). Interestingly, epitopes recognized by AMA and T-cell clones are located within overlapping areas of the antigens. Moreover,a role for an imbalance in cytokine pattern and for natural-killer lymphocytes has also been proposed. Despite several experimental reports, no clear evidence is available regarding the interaction of these factors leading to bile duct destruction. This article reviews the current reports regarding the auto-immune reaction against mitochondrial auto-antigens in PBC.

Antimitochondrial Antibodies and Reactivity to N. Aromaticivorans Proteins in Icelandic Patients with Primary Biliary Cirrhosis and Their Relatives

Primary biliary cirrhosis (PBC) is a chronic, progressive cholestatic disease of unknown etiology characterized by serum antimitochondrial antibodies (AMA) directed against a functionally related family of mitochondrial enzymes. We recently suggested that N. aromaticivorans might be the trigger of autoimmunity in PBC. No data are available on the specificity and crossreactivity of AMA in a genetically homogenous group of patients, such as the Icelandic population. To address these issues and to confirm previous findings in a unique population, we obtained sera from 14 PBC patients and 85 first-degree relatives, all of Icelandic descent. We analyzed such sera for AMA specificity using recombinant mitochondrial antigens and for reactivity against N. aromaticivorans proteins. Thirteen of the 14 Icelandic patients with PBC (93%) were found AMA positive. We found that 5/13 AMA positive sera (38%) reacted against PDC-E2 only; 5/13 (or 38%) reacted against BCOADC-E2; and 2/13 (15%) reacted against all three antigens. There was no reactivity against OGDC-E2. Reactivities of patients' sera against N. aromaticivorans were consistent with the AMA status. One serum among the 85 first-degree relatives (1.2%) was found to be AMA-positive, as well as reactive against N. aromaticivorans. Interestingly, despite the homogenous genetic background, the group of Icelandic patients with PBC was heterogeneous in their AMA reactive patterns and also reacted with N. aromaticivorans proteins.

Bacteria and human autoimmunity: the case of primary biliary cirrhosis.

Primary biliary cirrhosis is a chronic inflammatory disease of the intrahepatic bile ducts that eventually leads to liver cirrhosis and organ failure, in which several observations suggest an autoimmune origin. Similarly to other autoimmune diseases, microbial mediated molecular mimicry is the most widely studied trigger that may break immunologic tolerance in primary biliary cirrhosis. The hypothesis of a bacterial role in the cause of primary biliary cirrhosis has received recent attention, based on in vitro data and the identification of a unique xenobiotic-metabolizing bacterium that modulates naturally occurring environmental estrogens, namely, Novosphingobium aromaticivorans. The evidence indicates that bacteria, through different mechanisms, may precipitate autoimmunity in primary biliary cirrhosis and other autoimmune diseases. These data have several implications.

Autoimmunity and environmental factors in the pathogenesis of primary biliary cirrhosis

It is generally believed that autoimmune processes are initiated when tolerance to self‐proteins is broken. Primary biliary cirrhosis (PBC) is an autoimmune liver disease of unknown etiology. Autoimmune attack in PBC is predominantly organ‐specific, despite the presence of mitochondrial autoantigens, the major targets of autoimmunity in PBC, in all nucleated cells. Although the events that provoke initial activation remain unknown, the hypothesis of molecular mimicry implies that foreign pathogens with homology to self‐protein or modified self‐protein can break tolerance. Several reports have suggested the association of autoimmune diseases with drugs, chemicals, and other environmental factors. Specifically, many xenobiotics are metabolized in the liver. Liver autoantigens exposed to these chemicals could be modified and become immunogenic. We propose that exposure to the environmental xenobiotics is one of the initiating factors that leads to the loss of tolerance to self‐proteins in genetically susceptible hosts, resulting in development of PBC.

A population based study of autoimmunity in primary biliary cirrhosis (PBC) patients and their families: evidence for a shared susceptibility

A population based study of autoimmunity in primary biliary cirrhosis (PBC) patients and their families: evidence for a shared susceptibility

A population based study of autoimmunity in primary biliary cirrhosis (PBC) patients and their families: evidence for a shared susceptibility

A population based study of autoimmunity in primary biliary cirrhosis (PBC) patients and their families: evidence for a shared susceptibility

Combination therapy with mycophenolate mofetil and ursodeoxycholic acid for primary biliary cirrhosis

Evidence of autoimmunity in primary biliary cirrhosis (PBC) provides a rationale for treatment with an immunosuppressant. Such a drug should be sufficiently free from serious toxicities to enable patients with asymptomatic, but progressive, disease to be treated longterm. Mycophenolate mofetil (MMF) mediates immunosuppression by selectively and reversibly inhibiting lymphocyte function, and has a more acceptable safety profile than other immunosuppressants that have been used in the treatment of this disease. Two patients, whose response to long-term treatment with ursodeoxycholic acid (UDCA) had been inadequate, were treated with a combination of MMF 2 g daily and UDCA 1 g daily for 12 months. In both patients this regimen was associated with no clinically significant adverse events, a decrease in elevated serum alkaline phosphatase levels to values close to the upper limit of normal, and an almost complete disappearance of the chronic inflammatory cell infiltrate that had been present in pre-combination treatment liver biopsies. MMF may be an appropriate immunosuppressive drug for use in the long-term treatment of patients with PBC, including asymptomatic patients.

T-cell autoimmunity in primary biliary cirrhosis.

1. Primary biliary cirrhosis is a chronic cholestatic liver disease with an autoimmune aetiology. The classical histopathological lesion, of portal tract biliary epithelial cell damage, is accompanied by a T-cell-rich mononuclear cell infiltrate and upregulation of cell surface markers suggestive of local T-cell activation and cytokine release. This suggests that T-cell mediated mechanisms play an important role in tissue damage in primary biliary cirrhosis. 2. CD4+ T-cells specific for the E2 component of human pyruvate dehydrogenase complex (PDC-E2), a highly conserved enzyme which plays a critical role in intermediate metabolism, are present in the peripheral repertoire of the majority of patients with primary biliary cirrhosis. These cells are almost entirely absent from normal and chronic liver disease control subjects. The observations that peripheral blood PDC-E2-specific cells are most commonly seen in early stage disease, when active bile duct damage is occurring, and that PDC-E2- specific cells can be found in the portal tract infiltrate at times when this damage is occurring, suggest that these autoreactive cells may have a role to play in the aetiology of primary biliary cirrhosis. 3. T-cells specific for the whole PDC and its E1 component are seen in significant numbers of normal control subjects as well as patients with primary biliary cirrhosis. Retention of potentially autoreactive cells in the normal T-cell repertoire has been reported for a number of other autoantigens. 4. T-cell epitopes appear to be widely distributed throughout PDC-E2. This is in contrast to the B-cell epitopes which are highly restricted to the inner lipoyl binding domain of the protein.

T-Cell Autoimmunity in Primary Biliary Cirrhosis

T-Cell Autoimmunity in Primary Biliary Cirrhosis

Autoantibodies of primary biliary cirrhosis recognize dihydrolipoamide acetyltransferase and inhibit enzyme function.

Autoantibodies against mitochondria occur in the sera of patients with primary biliary cirrhosis (PBC) with characteristic reactivity to an inner membrane protein of approximately 74 kDa. To precisely define these autoantigens, we recently cloned and sequenced a rat liver cDNA (pRMIT) that encodes for all of the epitopes recognized by Ig to the 74-kDa autoantigen. In the present study we have used this recombinant probe as a tool, in addition to purified enzymes, to demonstrate by immunoblotting that the 74-kDa mitochondrial autoantigen is dihydrolipoamide acetyltransferase (EC 2.3.1.12), the core protein of the pyruvate dehydrogenase complex. Furthermore, and of particular interest, inhibition of pyruvate dehydrogenase enzyme activity was demonstrated after incubation with sera from patients with PBC but not from normal volunteers or patients with chronic active hepatitis. Such inhibition was abrogated by absorption of the PBC sera with an expressing subclone of pRMIT, designated pRMIT-603. Identification of dihydrolipoamide acetyltransferase as the target of autoimmunity in PBC provides a reagent that can be used to determine mechanisms by which this molecule is recognized. It will allow study of whether autoimmune reactivity, at the humoral or T cell level, is the basis for the pathogenesis of PBC. Additionally, such data present evidence of functional inhibition of a critical metabolic enzyme. Dihydrolipoamide acetyltransferase is well-known to mitochondrial biochemistry and, similar to identified autoantigens in other autoimmune diseases, is highly conserved in evolution.